A Comparison of Clinical Practice Guidelines in the Initial Pharmacological Management of New-Onset Epilepsy in Adults

OBJECTIVES: Clinical practice guidelines (CPGs) are intended not only to provide supportive information for health care providers but also to act as a guide for health care policy decisions. However, extant CPGs do not always reach the same conclusions. The objective of this study was to compare recommendations for initial pharmacological treatment of new-onset epilepsy in adults as stated within published CPGs. METHODS: We performed a systematic review of CPGs, which were published by prominent national organizations between January 2000 and June 2005, regarding the initial pharmacological treatment of epilepsy in adults. RESULTS: Five CPGs and 1 evidence report were identified that focus on pharmaceutical management in epilepsy. The 3 guidelines most relevant to the question of new-onset epilepsy treatment in adults were developed by the American Academy of Neurology (AAN), Scottish Intercollegiate Guidelines Network (SIGN), and National Institute for Health and Clinical Excellence (NICE). AAN recommends the use of both recently introduced antiepileptic drugs (AEDs: gabapentin, lamotrigine, topiramate, and oxcarbazepine) and standard agents (carbamazepine, phenytoin, valproic acid/divalproex, and phenobarbital) in newly diagnosed epilepsy, i.e., a nontiered approach. Alternatively, NICE recommends using newer AEDs (lamotrigine, topiramate, and oxcarbazepine) only in patients who derive no benefit from older agents a tiered approach. SIGN notes that all AEDs licensed for monotherapy have similar efficacy in newly diagnosed epilepsy a recommendation for a nontiered approach. The newer AEDs (lamotrigine and oxcarbazepine) are recommended as first-line initial treatment as are standard agents (carbamazepine and valproic acid/divalproex). The NICE guideline includes economic and quality-of-life evidence in their recommendations while AAN and SIGN do not. In these regards, current data fails to show superiority for newer agents. CONCLUSIONS: In the past 5 years, several CPGs have been published in epilepsy management. Only 3 guidelines have explicit recommendations for initial pharmacological treatment of adults with epilepsy. With some variation regarding which medications are recommended from each group, all CPGs promote standard and newer AEDs as having similar clinical efficacy. Until efficacy, quality of life, or cost data for the newer agents demonstrates a superior outcome, older AEDs remain viable options as first-line for monotherapy in newly diagnosed patients and may provide cost benefits over newer agents.

of epilepsy in adults. Specifically, we sought to answer the question "How do current, prominent guidelines compare in regard to recommendations for treatment of new-onset epilepsy in adults?" Thus, it does not address AED selection when treating refractory epilepsy, management of children, or any AED treatment patterns. It is intended to facilitate the practice of pharmacy benefit managers by providing information for policy-makers and to compare clinical treatment guidelines.

Search Strategy
A systematic review process was applied to obtain relevant CPGs that were published by prominent national organizations between January 2000 and June 2005 in the United States and other countries (published in English only). We did not include the guidelines that were published before the year 2000 because we considered them to be outdated. 6,7 The research question in this review was "What are the differences among guideline recommendations of new-onset seizure in adults?" National CPGs were identified by a computerized search from various sources, including electronic databases, (e.g., MED-LINE, PsycINFO, Cochrane Library, Current Contents, and Proquest Research Library), guideline Web sites (e.g., the U.S. National Guideline Clearinghouse [NGC], National Institute for Health and Clinical Excellence [NICE], Scottish Intercollegiate Guidelines Network [SIGN], Agency for Healthcare Research and Quality [AHRQ]), and hand searches of relevant journals. MeSH terms used were "epilepsy or seizure" with limits of "all adult: 19+ years," "publication date from 2000/1/1 to 2005/6/31," "English, practice guideline/ review," "humans." Other key search terms were "clinical practice guideline and epilepsy," "antiepileptic drug and epilepsy," "initial treatment and epilepsy," "review and drug treatment of new-onset epilepsy in adult," "monotherapy and newly diagnosed epilepsy," "drug management and newly diagnosed epilepsy," "first seizure," "new-onset epilepsy," and "first diagnosis."

Inclusion and Exclusion Criteria
Inclusion criteria regarding selection of CPGs were: (1) guidelines that are sponsored by governmental and prominent professional organizations, (2) publication in the English language, and (3) CPGs that address the role of AEDs in the initial management of epilepsy in adults (age >18 years). Exclusion criteria were: (1) CPGs in refractory epilepsy only, (2) CPGs of epilepsy treatment in childhood only, (3) any other examples of complex presentations of epilepsy that may be referred for specialist care, and (4) CPG does not address the research question "How do current prominent guidelines compare in regard to recommendations for treatment of new onset epilepsy in adults?" Searches of the reference lists and bibliographies of all papers for additional studies were performed as a part of the review.

Comparison of Clinical Practice Guidelines
Similarities and differences of the guidelines were evaluated and addressed to provide policymakers with information to support the use of CPGs in rational policymaking in the United States, focusing on the initial pharmacological treatment of new-onset epilepsy in adults.

II Results
Five national CPGs and 1 evidence report were identified from a systematic search according to the inclusion criteria. These CPGs included 3 from the United Kingdom (NICE, National Collaborating Centre for Primary Care [NCCP], and Joint Epilepsy Council [JEC]), 1 from Scotland (SIGN) and 1 from the United States (American Academy of Neurology [AAN]). [8][9][10][11][12] The evidence report was from AHRQ. 13 Characteristics of each are summarized in Table 1.
Although some guidelines included some exclusionary criteria such as recommendations for refractory symptoms or children, they were included because they addressed the primary research question. AAN, in conjunction with the American Epilepsy Society, addressed specific initial drug agent selection in the first part of its guideline. 12 SIGN provided complete recommendations for epilepsy management for both adults and children. The NICE guideline reviewed all aspects of newer drugs for epilepsy in adults. The NCCP guideline regarding newly diagnosed patients mirrors the NICE guideline; therefore, it was excluded to prevent redundancy. We also excluded the JEC guideline and AHRQ report because they do not have specific therapeutic recommendations for initial treatment of epilepsy. After excluding the guidelines from NCCP, JEC, and AHRQ according to our established criteria, the CPGs from AAN, NICE, and SIGN were included in the final comparison chart (see Table 2).

II Discussion
After comparing the guidelines, we found valid evidence that older, less-expensive AEDs still have an important role as firstline drugs of choice in adults with new-onset epilepsy; the role of newer AEDs is still controversial. SIGN and NICE guidelines contain recommendations to use AEDs as first-line treatment only under their licensed indications, while AAN recommendations include the use of AEDs that fall outside labeled FDA indications. 8, 11,12,15 AAN and SIGN also recommend the use of newer agents as first-line treatment in newly diagnosed patients. SIGN states, "Comparative, randomized, double-blind trials in patients with newly diagnosed partial and generalized tonicclonic seizures suggest similar efficacy for phenytoin, carbamazepine, sodium valproate, lamotrigine, and oxcarbazepine" and "The newer AEDs, lamotrigine and oxcarbazepine, seem to be better tolerated and may produce fewer long-term side effects and adverse interactions." 11 These recommendations are consistent with other scientific literature. 16   use of the older AEDs and clearly states that newer AEDs should be second-line in initial treatment, based upon a lack of goodquality evidence from clinical trials to support the preferential use of newer AED monotherapy over the older drugs. They state, "Almost all studies comparing newer drugs with older drugs have found no statistically significant differences in terms of seizure-related outcomes…. However, it cannot be concluded that the drugs have been shown to be equivalent in terms of efficacy…." 8 "One important clinical question for the treatment of newly diagnosed patients is whether lamotrigine, oxcar-bazepine, and topiramate are more effective than older AEDs. This review found insufficient evidence from good-quality clinical trials to answer this question." 15 NICE suggests that a review of the adverse events and tolerability from clinical trials does not provide sufficiently consistent results necessary to draw conclusions to support a preference for the newer AEDs compared with the older ones.
Important information uniquely found in NICE is the health-related quality-of-life (HrQoL) evidence review. Quality of life is an important advantage proposed for the newer AEDs.  NICE states, "However, only nine of the 19 studies comparing monotherapy using newer drugs versus older drugs assessed quality-of-life" and "These studies do not provide strong evidence of improved quality of life with the newer drugs." 8 Based on a broader review of the literature, NICE concludes that there is insufficient evidence to confirm an advantage for the newer AEDs over the older agents related to their ability to improve patients' HrQoL. AAN did mention in its guideline that "… the burden is on the treating physician to select the AED that is the most tolerable, has the lowest potential for harm, and has the least likelihood of negatively impacting quality of life"; however, AAN did not included this parameter in its review.

Guidelines Selected for Clinical Review Inclusion. Recommendations Regard the Initial Medication Choice With Typical Maintenance Dosing for Epilepsy in Adults
The NICE guideline declares that the evidence on costeffectiveness considered by the reviewing committee indicates that none of the published economic evaluations satisfied the criteria for a robust economic evaluation, but monotherapy with the older AEDs is considerably less expensive, considering only drug cost. 15 They state, "Even when the most optimistic treatment scenario for the newer drugs was compared with the worst-case treatment scenario for the older drugs, monotherapy with the older drugs was considerably less costly." 8 Finally, they conclude that "the older monotherapies appeared to be cost effective when compared to newer AEDs for the treatment of newly diagnosed patients experiencing generalised seizures." 15 When comparing U.S. and European studies, a limiting factor is the insufficient cost-effectiveness and HrQoL information for AEDs used as initial treatment of epilepsy in the United States. AAN states, "The older AEDs have an advantage of broad familiarity, lower cost, known efficacy, wide availability via coverage by third-party payers, and long-term experience" and "The new drugs are all substantially more expensive than the old. There is no literature that addresses the cost-benefit related to these issues." 12 In the United Kingdom, NICE asks pharmaceutical companies to submit both published and unpublished information to incorporate into the CPG. 15 This provides a broader foundation for the examination of cost-effectiveness and HrQoL assessments. Although the AHRQ guideline includes costs and HrQoL in its review, it does not have recommendations regarding these issues for newer AEDs. 13 The AAN guideline recommends 4 newer AEDs (oxcarbazepine, gabapentin, lamotrigine, and topiramate) as first-line drugs along with the older agents. Notable is that 3 of these AEDs (except for oxcarbazepine) are not approved in the United States for monotherapy of newly diagnosed patients. AAN states, "The FDA does not accept such a finding as proof of efficacy, due to the possibility that two ineffective drugs might also exhibit no difference in effect when compared against one another. For the purpose of this parameter, we accepted the demonstration of equivalence between an established AED such as carbamazepine or phenytoin and a new drug as confirmation of effectiveness." 12 The FDA uses placebo-controlled clinical trials to evaluate the use of new AEDs as monotherapy in initial treat-ment of newly diagnosed epilepsy. 17 This type of trial can present an ethical dilemma to investigators who must randomize newly diagnosed patients to the placebo arm. In the recommendation for future research, AAN states "There is no doubt that the ideal methodology for detecting drug effect in most cases is to use a placebo/control comparison. However, because trials in patients with newly diagnosed epilepsy must be performed, by definition, in the monotherapy condition, there are ethical concerns regarding a placebo or substandard control in this population. Therefore, comparative trials remain the preferred tactic. Clinicians favor these trial designs" and "…these trials are not acceptable for registration purposes in the United States, as the FDA has required demonstration of superiority…. Discussion is ongoing as to how to resolve this conflict between the needs of the clinician and the needs of regulatory bodies." 12 The United Kingdom and some countries in Europe accept active-control studies to approve monotherapy indication of new AEDs. 17 This may contribute to an explanation as to why AAN recommendations of newer AEDs differ from licensed indications in the United States.
Beghi, in 2004, published a comparison of AAN and NICE guidelines. 18 His review included the use of newer AEDs in the treatment of epilepsy for both adults and children as well as in special populations (children and patients with learning disabilities and intellectual deficits, women of childbearing age, the elderly). Yet, the paper mainly focused on the place in therapy of newer agents according to these recent guidelines. He concluded that "Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendation." And "The U.K. guidelines are more conservative when compared to the U.S. guidelines." When evaluating specific recommendations from CPGs, it is crucial to understand the rationale for excluding CPGs whose recommendations are not considered. This permits a more transparent understanding of the potential for bias in the recommendations used in managed care. In this paper, we attempted to model this as a practice that should be employed when using CPG recommendations to inform drug policy decisions. Policymakers tend to utilize the findings or recommendations from research evidence sources that are clear in content, valid, and up-to-date. 19,20 The differences among CPGs recommendations present a dilemma to those trying to make drug policy decisions with an evidence-based approach and limit utilization of newer AEDs for maximum patient benefit. The variation among these CPGs might be a result of the process of guideline development. An evidence review to assess the treatment pattern of epilepsy management might be of interest, but it is beyond the scope of this paper. However, we could find no literature review regarding managed care in the U.S. practice. Since pharmacoeconomics and HrQoL are obvious www.amcp.org Vol. 12 concerns of policymakers, future research should evaluate the cost-effectiveness and HrQoL of the initial AEDs treatment in adult patients with new-onset epilepsy in the United States to support drug policy decisions.

II Conclusion
From our review of current CPGs for AEDs in the initial pharmacological management of epilepsy in adults published in the past 5 years, we found that the older AEDs, including carbamazepine, phenytoin, and valproic acid, still play an important role as first-line monotherapy for management of new-onset epilepsy in adults. Until cost-effectiveness data or quality-of-life studies show a convincing benefit for newer agents, they should remain second-line.

DISCLOSURES
No outside funding supported this study. The authors disclose no potential bias or conflict of interest relating to this article. Author Nalin Payakachat served as principal author of the study. Study concept and design were contributed by Payakachat and authors Kent H. Summers and John P. Barbuto. Data collection was the work of Payakachat; data interpretation was primarily the work of Payakachat, with input from Summers and Barbuto. Drafting of the manuscript and its revision was primarily the work of Payakachat, with input from Summers and Barbuto.